Researchers at the University of California, San Francisco, have drawn a link between distinctive genetic abnormalities in some neurodegenerative diseases and the formation of “RNA foci,” abnormal clusters of ribonucleic acid (RNA) molecules that accumulate in the cell nucleus.
The presence of RNA foci is a prominent feature of a group of deadly inherited neurodegenerative diseases, including Huntington’s disease, certain forms of amyotrophic lateral sclerosis (ALS), and frontotemporal dementia.
While many researchers believe that these clusters are toxic to nerve cells, it has not been clear how or why they form.
Published online recently in the journal Nature, the new study focused on a group of disorders known as “repeat expansion” diseases. In these conditions, short strings of the deoxyribonucleic acid (DNA) “letters” known as nucleotides are abnormally repeated several times.
Over the course of an individual’s life, or across generations, the number of such repeats can expand, which may increase disease susceptibility and severity within families.
Another suspect is messenger RNA, which is copied from the DNA and used by the cell to guide protein production.
Ronald Vale, professor in the UCSF’s Department of Cellular and Molecular Pharmacology, who led the new research, and UCSF postdoctoral fellow Ankur Jain, who performed the new experiments, found that each nucleotide repeat in RNA behaves like a small piece of molecular Velcro, or fastener, that can stick to repeats on other RNA strands.
“When you have lots of tandem pieces of Velcro, that allows one RNA strand to stick to multiple other strands with similar repeats,” Vale said. “What you then get is many RNAs binding to one another to form a tangled gel.”
Jain and Vale demonstrated this phenomenon in purified RNA in a test tube as well as when they artificially induced production of these disease-causing RNAs in cells in a dish.
“You start that process of making the RNA in cells and then can watch the gels forming in the nucleus in a time-lapse movie,” Vale was quoted as saying in a news release.
And the two researchers found that about 30 nucleotide repeats were needed to trigger formation of RNA gels, similar to the number of repeats associated with the emergence of disease symptoms.
RNA gels did not form when Jain tested random nucleotide sequences that did not have disease-related repeating patterns.
In addition, while previous research indicated that RNA somehow combined with proteins to form foci, the new research suggests these clusters can arise from RNA alone.
“We have contributed a new hypothesis of how RNA foci form in these disorders,” said Vale. “Protein aggregation is a well-accepted cause of many neurodegenerative diseases, including Alzheimer’s and ALS, but our work suggests that aggregation of RNA, by itself, might also be a culprit in neurodegeneration.”
“Now we want to tackle new therapeutics by focusing on strategies that act on RNA and that could dissolve these potentially pathological structures,” he said. Enditem